Project Summary Atrial fibrillation (AF) is the most common arrhythmia affecting well over 2 million people in the US with projections that it will affect 8-12 million people by 2050. It is responsible for >$6 billion in annual health care expenditures in the US. Catheter ablation to achieve sinus rhythm is a growing therapeutic option due to its greater success rate compared to antiarrhythmic drug therapy. Yet, success rates for catheter ablation are suboptimal. For patients with persistent AF, catheter ablation has even lower success rates than for those with paroxysmal AF. The STAR AF II randomized multicenter clinical trial reported an average freedom from AF after one procedure of 50% for patients with persistent AF. Epicardial adipose tissue (EAT) may play an independent role in the progression, development and recurrence of AF after catheter ablation. Specifically, left atrial (LA) EAT due to its contiguity to the LA may directly influence LA substrate via inflammatory, profibrotic, and other adipocytokines. Liraglutide (a glucagon like peptide-1 analog), an effective therapy for obesity and diabetes, markedly reduces EAT. A combined medical approach for substrate stabilization with catheter ablation has not been evaluated. Thus, the overall goal of this project is to assess the novel approach of substrate stabilization as adjunctive therapy in patients with persistent AF undergoing catheter ablation. We hypothesize that Liraglutide treatment will significantly reduce LAEAT and consequently stabilize (and even perhaps ameliorate) AF substrate. Our specific aims are to: 1) Assess for serial changes in LAEAT, EAT, atrial size/function and biomarkers of inflammation in patients with persistent AF who opt for catheter ablation due to Liraglutide treatment; 2) Evaluate the correlation of LAEAT to LA biomarkers. We will enroll 60 patients with persistent AF who have elected to undergo catheter ablation. Pre-ablation therapy will include: 1) antiarrhythmic drug therapy and cardioversion (if needed) to promote reverse electrical remodeling; 2) Risk factor management; 3) Half will be randomized to receive Liraglutide. After pre-treatment for 3 months, catheter ablation will be performed using an antral pulmonary vein isolation based approach. The primary endpoint will be change in LAEAT at 3 months (prior to ablation). Substrate evaluation will include CT (EAT, LAEAT), echocardiography (strain, EAT thickness), and biomarkers at enrollment, pre-ablation, and at one year. We will assess freedom from AF at one year off antiarrhythmic drugs documented by long-term event monitoring and compare baseline LAEAT. Evaluating the broad array of imaging and blood biomarkers will help delineate parameters that can be used to track substrate stabilization therapy. Thus, this open label clinical study of Liraglutide in combination with catheter ablation for AF will provide foundational data that will be critical for the further testing and validation of this novel approach, one that could substantially improve outcomes for patients with AF.